Multiple myeloma (MM) is an aggressive form of blood cancer with over 22,000 new cases each year. Current therapies are based upon inhibition of the proteasome, a multi-protein enzyme that performs a multitude of essential cellular activities. Most importantly, the proteasome is responsible for degrading misfolded and/or non-functioning proteins. Inhibition of the proteasome leads to cell death; hence, this enzyme is a valid target for cancer therapy. Proteasome inhibitors are especially effective against MM because this cancer has been shown to express exceptionally high levels of this protein complex. Unfortunately, resistance to the previously developed proteasome inhibitors that target the catalytic portion of the proteasome responsible for protein degradation has evolved rapidly leaving patients with few alternative treatments. A new therapy that still takes advantage of MM's susceptibility to proteasome inhibitors, but that functions by a novel mechanism of action is needed. To address this challenge, we propose to target a different subunit of the proteasome, namely the 19S regulatory particle (RP). The 19S RP is responsible for recognizing and shuttling proteins for degradation to the catalytic core of the proteasome. To date, no small molecule inhibitor of the human 19S RP has been developed. The objective of this training fellowship is to identify a 19S RP inhibitor through the synthesis of a large combinatorial library of constrained peptidomimetic oligomers (CPIOs) and application of assays for determination of the binding ability and activity inhibition of our CPIOs. The CPIO library wil utilize synthetic techniques developed for peptides and peptoids but will incorporate moieties found in natural products since these compounds are often bioactive and are typically much more potent than standard peptides/peptoids. We will generate CPIOs with numerous stereocenters and backbone rigidity, characteristics that have not been previously explored. Initial hits will be determined using a binding assay to facilitate rapid screening of our large library against the 19S RP. Next, CPIOs that bind to the 19S RP will be tested for enzyme activity inhibition. Finally, the most potent CPIO inhibitors will be subjected to MM cell lines, bth resistant and susceptible to proteasome inhibitors, for determination of their ability to induce cel death. We anticipate that our novel library of small molecules will lead to the identification of a 19S RP inhibitor, providing a potential new treatment for MM.